Biology subjects

Zatzman, M.

Publications and source records attributed to Zatzman, M..

3 recordsLinked to original sources

bioRxiv2025

Complementary modes of resistance to EGFR TKI in lung adenocarcinoma through MAPK activation and cellular plasticity

EGFR-mutant lung adenocarcinoma (LUAD) represents 20% of all non-small cell lung carcinomas, with most patients presenting with incurable metastatic disease. Treatment with mutant-selective EGFR tyrosine kinase inhibitors (TKIs) results in initial tumor reduction, yet nearly all patients eventually relapse. The mechanisms driving drug resistance are incompletely understood, creating significant barriers to curing metastatic disease. We integrated clinical genomic and single-nuclei RNA (snRNA) sequencing from a cohort of 62 EGFR-mutant LUAD patients treated with the third generation EGFR TKI, osimertinib, and compared treatment-naive (TN), minimal residual disease (MRD), and progressive disease (PD) tumors. We found that disease progression is associated with a marked decrease in alveolar lineage fidelity, coincident with reduced MAPK signaling and adenocarcinoma identity. PD tumors with sustained MAPK pathway activity, such as those with EGFR or MET amplifications, tended to retain adenocarcinoma identity. In contrast, MAPK-low tumors were more likely to undergo histological transformation to squamous or neuroendocrine lineages. Remarkably, we observed rare tumor cell populations prior to treatment that were poorly differentiated, in some cases with neuroendocrine or squamous features. At progression, these histologically divergent tumor cells increased in prevalence, both in cases with overt histological transformation, and in others with sub-clinical histological plasticity. These findings suggest that pre-existing capacity for histologic plasticity may be a substrate for therapy induced selection. Taken together, our results illuminate genomically encoded MAPK signaling and lineage plasticity as complementary mechanisms of acquired resistance to EGFR TKI in lung adenocarcinoma.

cancer biology↗

bioRxiv2024

Tracking clonal evolution of drug resistance in ovarian cancer patients by exploiting structural variants in cfDNA

Drug resistance is the major cause of therapeutic failure in high-grade serous ovarian cancer (HGSOC). Yet, the mechanisms by which tumors evolve to drug resistant states remains largely unknown. To address this, we aimed to exploit clone-specific genomic structural variations by combining scaled single-cell whole genome sequencing with longitudinally collected cell-free DNA (cfDNA), enabling clonal tracking before, during and after treatment. We developed a cfDNA hybrid capture, deep sequencing approach based on leveraging clone-specific structural variants as endogenous barcodes, with orders of magnitude lower error rates than single nucleotide variants in ctDNA (circulating tumor DNA) detection, demonstrated on 19 patients at baseline. We then applied this to monitor and model clonal evolution over several years in ten HGSOC patients treated with systemic therapy from diagnosis through recurrence. We found drug resistance to be polyclonal in most cases, but frequently dominated by a single high-fitness and expanding clone, reducing clonal diversity in the relapsed disease state in most patients. Drug-resistant clones frequently displayed notable genomic features, including high-level amplifications of oncogenes such as CCNE1, RAB25, NOTCH3, and ERBB2. Using a population genetics Wright-Fisher model, we found evolutionary trajectories of these features were consistent with drug-induced positive selection. In select cases, these alterations impacted selection of secondary lines of therapy with positive patient outcomes. For cases with matched single-cell RNA sequencing data, pre-existing and genomically encoded phenotypic states such as upregulation of EMT and VEGF were linked to drug resistance. Together, our findings indicate that drug resistant states in HGSOC pre-exist at diagnosis and lead to dramatic clonal expansions that alter clonal composition at the time of relapse. We suggest that combining tumor single cell sequencing with cfDNA enables clonal tracking in patients and harbors potential for evolution-informed adaptive treatment decisions.

cancer biology↗

bioRxiv2024

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime, we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily active mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

cancer biology↗